I probably should have posted the quote. What I meant is that he said folinic acid would lower glutamate because it's polyglutamated (or at least he thought it was at one time). I didn't want to post it here because like I said I wasn't sure if it was accurate since he only mentioned it once in 2010 (even though he talked about glutamate induced excitotoxicity many times since then). This is what he said:"Another factor is that folinic acid is polyglutamated when it is inside the cells, and this can help to lower the amount of free glutamate, which is an excitotoxin."

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Let me correct something in my earlier reply. Only monoglutamate forms can enter cells but both folinic acid and methylfolate inside celks are polyglutamated. I think this is true of other intracellular folate derivatives as well. Hence why most ingested dietary folates are polyglutamated. That being said in animals methylfolate is the dominant circulating form of folate. I also stick by my assertion that fokate derivative distributions between plants and animals are very different. On the other hand any glutamate lowering effects of folinic acid or methyfolate is likely due to other mechanisms not simply intracellular storage. Besides excitotoxicity is about extracellular glutamate in the neuronal gap not inside the cells. Hence the reason people drink coffee. As an aside I see people post that they have perceived glutamate excitoxicity but drin coffee ... if glutamate was overloaded then drinkinf coffee would set off a firestorm. Had that happen twice due to coffee. Both times I wanted basically to die.

As an aside I see people post that they have perceived glutamate excitoxicity but drin coffee ... if glutamate was overloaded then drinkinf coffee would set off a firestorm. Had that happen twice due to coffee. Both times I wanted basically to die.

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Hmm. I guess I'm misunderstanding something, as this says caffeine is good for excitotoxicity.

Caffeine
Regular coffee drinkers are at markedly lower risk for Parkinson’s disease [169], and two epidemiological studies suggest that Alzheimer’s disease may also be less common in coffee drinkers [170,171]. Caffeine has well documented neuroprotective effects in a range of rodent models, including those for Parkinson’s disease,
stroke, and excitotoxicity [172]; moreover, caffeine is reported to decrease the toxicity of b amyloid to cultured cerebellar neurons in vitro [173]. This protection appears to reﬂect inhibition of adenosine type 2A receptors (A2A), widely expressed in the brain [172]. In particular, such receptors are found on microglial cells, and selective agonists for this receptor promote induction of COX-2 in these cells [174]. Thus, it is conceivable that caffeine neuroprotection reﬂects, at least in part, down-regulation of COX-2 expression in microglia. However, the main impact of A2A antagonists on neurodegeneration may reﬂect a down-regulation of glutamate release from excitatory synapses; evidently, adenosine plays a physiological role in promoting the extracellular glutamate excess that mediatesexcitotoxicity [175–178].

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I concede that my glutamate issues are indeed "perceived" - I have no proof that is what drives my problem. But something makes my brain to go haywire, and it correlates with known excitotoxins - but caffeine is not one of them.

Dietary folates are technically any folate derivative. But the majority ingested from plants is not THF, not folinic acid, and not l5mtthf. They are simply folate (the natural non oxidized polyglutamated form of folic acid). It is pretty clear if you look at the diagram in the link I put in my post. So no plant folates is NOT meat methylfolate. I never said that sorry.

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Other people have said the folate in meat is methylfolate. I wasn't referring to anything you said. I just asked because I figured you probably knew the answer.

I understand your reluctance about methylfolate but if you really are processing the folic acid than the endgame is essentially to convert to methylfolate ignoring the parts that get drained into making DNA / RNA. You may be reacting to methyl donors of any type.

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I'm not sure what happened. I was taking 1600+ folic acid, 200 mcg methylcobalamin orally, and TMG (as betaine hcl), but as soon as I started taking methylfolate I had serious problems. I also do have problems with too much sublingual B12 (without folate). That could partially be due to the fact that I do get a lot of dietary folate including some from meat.

My plan is to slowly increase folinic acid first since it serves other functions besides converting to methylfolate, but mainly because there's some b complexes and multivitamins with only folinic acid which I'd like to take instead of taking all my b vitamins separately and/or taking b complexes with folic acid. Even if I am converting folic acid to active folates (it certainly didn't block methylfolate), folic acid still uses up NADPH and ties up the DHFR enzyme which is needed for BH4. I'm just not sure if 100-200 mcg of folic acid is enough to cause problems.

This may suggest inflammatory processes

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Rich said inflammation from methylation could be from infection. Do you know if there are other reasons why methylation can cause inflammation? And does it still cause inflammation even if you're not overmethylating?

or maybe COMT++ intolerance.

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My 23andMe results will be here in 6-8 weeks so you're welcome to place bets. Just a side note on that. My saliva for the test kit was slightly yellow due to a sublingual I took earlier. I didn't feel like doing the saliva sample again so I just sent it in. Now I'm sort of freaking out that it will mess up the results.

Before you got sick, what was your mood generally like? Happy a lot? So much so it made other people sick? A lot of drive? Mental energy? Just curious.

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First you're my doctor, now my psychiatrist? Ok, I'll humor you I guess. I was very active and athletic when I was young. I wasn't really driven academically until I got to high school, but I was into sports and video games before that. I think I have Asperger's to a certain degree. At least 2 online tests I took say I have Asperger's. I was bullied in elementary school so I think I was mildly depressed since then. Assuming my tick bite at age 16 was where my illness began, within a year or two I was severely depressed and had major insomnia. I've had insomnia my whole life though. I do have a lot of mental energy. I wouldn't say I have much mental anxiety, but I do have an active mind. I have both ADD and OCD to a certain extent so my research is a bit chaotic to say the least.

I concede that my glutamate issues are indeed "perceived" - I have no proof that is what drives my problem. But something makes my brain to go haywire, and it correlates with known excitotoxins - but caffeine is not one of them.

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NE and ammonia are other possibilities for example. You can read some other posts distinguishing NE vs glutamate.

Sorry I don't buy that article. Caffeine affects glutamate transport flooding the extracellular gap so the neurons fire and people feel "good" mentally. Of course there is tolerance that builds up but that is a separate issues.

They are talking about something very different. Different pathway. They are talking about microglial activation which is the CNS equivalent of immune cells and inflammation. Very important to neurodegenerative disorders. Does not invalidate the heightened activity of GLT transporters.

I'm not sure what happened. I was taking 1600+ folic acid, 200 mcg methylcobalamin orally, and TMG (as betaine hcl), but as soon as I started taking methylfolate I had serious problems. I also do have problems with too much sublingual B12 (without folate). That could partially be due to the fact that I do get a lot of dietary folate including some from meat.

My plan is to slowly increase folinic acid first since it serves other functions besides converting to methylfolate, but mainly because there's some b complexes and multivitamins with only folinic acid which I'd like to take instead of taking all my b vitamins separately and/or taking b complexes with folic acid. Even if I am converting folic acid to active folates (it certainly didn't block methylfolate), folic acid still uses up NADPH and ties up the DHFR enzyme which is needed for BH4. I'm just not sure if 100-200 mcg of folic acid is enough to cause problems.

Rich said inflammation from methylation could be from infection. Do you know if there are other reasons why methylation can cause inflammation? And does it still cause inflammation even if you're not overmethylating?

My 23andMe results will be here in 6-8 weeks so you're welcome to place bets. Just a side note on that. My saliva for the test kit was slightly yellow due to a sublingual I took earlier. I didn't feel like doing the saliva sample again so I just sent it in. Now I'm sort of freaking out that it will mess up the results.

First you're my doctor, now my psychiatrist? Ok, I'll humor you I guess. I was very active and athletic when I was young. I wasn't really driven academically until I got to high school, but I was into sports and video games before that. I think I have Asperger's to a certain degree. At least 2 online tests I took say I have Asperger's. I was bullied in elementary school so I think I was mildly depressed since then. Assuming my tick bite at age 16 was where my illness began, within a year or two I was severely depressed and had major insomnia. I've had insomnia my whole life though. I do have a lot of mental energy. I wouldn't say I have much mental anxiety, but I do have an active mind. I have both ADD and OCD to a certain extent so my research is a bit chaotic to say the least.

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That is a lot of folic acid with just a bit of mb12, especially oral. Adding methylfolate on top of that is begging for a folate trap imo. DIetaty folate in meat is extremely small. We already discussed the forms you get in veggies. I eat 3500-4000 calories a day all meat, nuts, and veggies with a bit of fruit and the total amount of folate is under 350 mcg or so. Not much.

Give the folinic acid a try. If you took folic acid before you probably can convert it. But now too much may mean too much ATP required. I doubt 100 mcg is going to wreck things given you took higher doses in the past.

I am neither your doctor nor your psychiatrist. The questions I asked about mood were specific to COMT. That is all I was asking about, sorry. I intended no insult.

People with COMT mutations tend to be more joyful, ebullient, and happy but can be prone to mood swings especially if coupled with MAO mutations. They tend to have very high dopamine and NE levels, summoning NE to get tasks done, etc. We will have to see what your tests show.

Rich said inflammation from methylation could be from infection. Do you know if there are other reasons why methylation can cause inflammation? And does it still cause inflammation even if you're not overmethylating?

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I would substitute any chronic inflammatory disorder for infection (i.e. autoimmune, heavy metal burden, etc.) Anything that has the immune system going. One mechanism that hypermethylation might exacerbate underlying inflammation is via catecholamine production and specifically NE. Multiple doctors (yasko, Lynch, Neubrander, etc.) warn that from clinical observations underlying inflammation can be made worse with methylation. That being said they don't maybe factor in the role of adb12 for example or the importance of ATP generation . Certainly high levels of methylfolate both exacerbate my potassium excretion and increase methylation for me with my autoimmune disease. It is all about finding the balance.

NE and ammonia are other possibilities for example. You can read some other posts distinguishing NE vs glutamate.

Sorry I don't buy that article. Caffeine affects glutamate transport flooding the extracellular gap so the neurons fire and people feel "good" mentally. Of course there is tolerance that builds up but that is a separate issues.

They are talking about something very different. Different pathway. They are talking about microglial activation which is the CNS equivalent of immune cells and inflammation. Very important to neurodegenerative disorders. Does not invalidate the heightened activity of GLT transporters.

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True. I have amassed a lot of links to random papers regarding glutamate and I remembered that one when you mentioned coffee, but you're right - it's a different pathway.

Well, I can tell when it's NE because there's both a physical and mental reaction, but telling the difference between glutamate and ammonia.. no idea. It could be both, for all I know. As I said, I have trouble with even small amounts of known excitotoxins, but no issue at all with a reasonable amount caffeine. But I also have excitotoxicity issues seemingly out of nowhere, which unfortunately makes the source/cause hard to pin down.

People with COMT mutations tend to be more joyful, ebullient, and happy but can be prone to mood swings especially if coupled with MAO mutations. They tend to have very high dopamine and NE levels, summoning NE to get tasks done, etc. We will have to see what your tests show.

That is a lot of folic acid with just a bit of mb12, especially oral. Adding methylfolate on top of that is begging for a folate trap imo.

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Just so I don't seem like a total methylation n00b, I was taking 1600 mcg folic acid and 200 mcg methylcobalamin orally before I learned about methylation. My multi had 800 mcg folic acid and my b complex had 400 mcg folic acid/100 mcg methylcobalamin which I took twice a day. My first methylation "attempt" was unintentional. The company simply added 50 mcg of methylfolate to the formula. So I was taking that twice a day for a total of 100 mcg methylfolate and no other methyl donors except the 200 mcg oral dose of methylcobalamin and 1000+ mg of TMG (as betaine hcl). That was enough to cause serious problems. I didn't go into detail because I've mentioned this a few times already in various threads.

DIetaty folate in meat is extremely small. We already discussed the forms you get in veggies. I eat 3500-4000 calories a day all meat, nuts, and veggies with a bit of fruit and the total amount of folate is under 350 mcg or so. Not much.

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I mentioned it only to try explain why such a low dose of B12 seems to affect me even though until recently I wasn't taking any other folate except from food. And the other only methyl donor being betaine hcl. I don't know much about SNPs, but based on my sensitivity to even hydroxocobalamin it seems likely that I'm COMT. Probably my current state of health also affects how I respond to methylation supplements. If I had tried methylation a year ago when I was making a recovery maybe I would have had an easier time.

I am neither your doctor nor your psychiatrist. The questions I asked about mood were specific to COMT. That is all I was asking about, sorry. I intended no insult.

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I wasn't insulted. Just a little surprised, but I know you well enough to assume you were going somewhere with it. I can understand why you want to back away from being labeled "doctor" with liabilities and whatnot, but I just making a joke. You do seem to know more than my doctor and she's the best doctor I've ever had, but again I don't actually consider you "giving me medical advice" so don't worry. I really do appreciate your in-depth answers though. I've learned so much in such a short amount of time. And yet it seems there's so much left to learn. I told you before that you seem to have an answer for every question. Well, I seem to have a question for every answer.

People with COMT mutations tend to be more joyful, ebullient, and happy

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I probably was like that as a young kid, but I also had a hard time adjusting to life even before my illness. It's hard to say what my true personality is. Like I said before, I have Asperger's to a certain extent coupled with depression at an early age so it's hard to know who I really am.Happy a lot? So much so it made other people sick?
In my late teens/early 20s I got high on a semi-regular basis and I think that was my personality. I probably was annoying to be around some of the time. Maybe that was my true personality.

but can be prone to mood swings especially if coupled with MAO mutations. They tend to have very high dopamine and NE levels, summoning NE to get tasks done, etc. We will have to see what your tests show.

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In high school and college I was very active. I was in the honors program, played sports, worked part time, did theater. It was only a matter of time until my crash, but even after I started getting sick I kept pushing myself. I've been running on empty for a long time. I assume it's the NE giving me the "energy" based on what you've said to me in the past. Since my relapse at the end of last summer my blood pressure has been getting higher even though I'm on Lisinopril. It doesn't seem like a coincidence that my NE symptoms started around the same time.

True. I have amassed a lot of links to random papers regarding glutamate and I remembered that one when you mentioned coffee, but you're right - it's a different pathway.

Well, I can tell when it's NE because there's both a physical and mental reaction, but telling the difference between glutamate and ammonia.. no idea. It could be both, for all I know. As I said, I have trouble with even small amounts of known excitotoxins, but no issue at all with a reasonable amount caffeine. But I also have excitotoxicity issues seemingly out of nowhere, which unfortunately makes the source/cause hard to pin down.

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Do you have CV symptoms with BP and pulse when you are wired? Or is it more sensory related? Just curious.

I wasn't insulted. Just a little surprised, but I know you well enough to assume you were going somewhere with it. I can understand why you want to back away from being labeled "doctor" with liabilities and whatnot, but I just making a joke. You do seem to know more than my doctor and she's the best doctor I've ever had, but again I don't actually consider you "giving me medical advice" so don't worry. I really do appreciate your in-depth answers though. I've learned so much in such a short amount of time. And yet it seems there's so much left to learn. I told you before that you seem to have an answer for every question. Well, I seem to have a question for every answer.

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Ok. I wasn't looking to pry or find out about your mental state. It was a simple question about what your personality tended to be. I see it simply as a clue about neurotransmitters. Personal history was not my objective.

For example, a synopsis for myself: all my life until my health deteriorated I was very type A, very driven, athletic, occasional mood swings, very successful in my business endeavors and very good in social situations though I prefer to be with family or core friends when left to my own devices. I look back at it and I can say I was always using NE to accomplish things, generally high DA type, always had issues with sleep since high school, and low GABA.
In my case I know who I am it is just that I had it all taken from me with my autoimmune disease. That is my story.

In high school and college I was very active. I was in the honors program, played sports, worked part time, did theater. It was only a matter of time until my crash, but even after I started getting sick I kept pushing myself. I've been running on empty for a long time. I assume it's the NE giving me the "energy" based on what you've said to me in the past.

Neuropsychology plays a major role in all this. All by itself lack of MeCbl/AdoCbl/methylfolate can cause a multitude of mood and personality symptoms ranging from mild depression to the most extreme psychosis. Those with these CFS/FMS/ME symptoms and anxiety are often hypersensitive to l-carnitine. Carnitine can set of a series of "moods" from anxiety, fear, panic, anger, rage and homicidal rage then to extreme depression all following the CSF serum level of carnitine first up and then down. The "Parkinson's personality" appears ties to AdoCbl and carnitine in the limbic system of the brain. Parkinson's has limbic damage. The exact responses to lack of these nutrients often depends upon where the demyelinations occur. Those that split out on more predominant MeCbl and methylfolate (and unknowns) deficiencies tend towards MS and Subacute Combined degeneration and often have a to some degree a euphoric response to MeCbl, AdoCbl, l-carnitine and methylfolate as compared with the anxiety, fear, and rage sequence. For some percentage of people these personality and mood characteristics are apparent in early childhood. OCD and bipolar appear to shoehorn into this too but the placement of it is not as clear.

When the CNS damage is healing the moods and personality characteristics can be extremely volatile and changes can happen daily for 6-9 months following a change that starts affecting these CNS areas. A person can go through several such sequences as they add additional factors. I had at least 4 rounds of such healing, each with a different key nutrient of the Deadlock Quartet as it was added.

The described responses to the nutrients can generally be predicted based on questionnaire answers. Between methylation and ATP every hormone, every neurotransmitter and the functionality of the neurons themselves are affected. Honestly this is far more physiological and less psychological than I ever imagined when I was studying comparative and physiological psychology. The changes can be as pronounced and sudden as when RF or thermal lesions are made in the brain experimentally.

Do you have CV symptoms with BP and pulse when you are wired? Or is it more sensory related? Just curious.

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I occasionally have a strong, unwarranted stress response (heart pounding, extreme restlessness(akathisia?), anxiety, paranoia) to some small thing, or sometimes there is no stressor at all. The out of nowhere attacks usually happen at night. This is different than when my mind is racing but I have no physical reaction - over the years I've begun to associate this with excitotoxicity from something I've consumed.

Back to the study which seems to have used anywhere from 25-100 mg of folinic acid. I still don't understand what the point is of using such a high dose of folinic acid does. The main thing Rich talked about is that folinic acid is used to create nucleotides, but are there other reasons that it's useful? Is going above 1000 mcg really going to make much of a difference? And is there a limit to how much will be converted into methylfolate? Even for the people who are able to process folinic acid, would the mega-doses of 25000 (or even 5000) still block methylfolate due to the high amount in their system? Would it still pile up even if they are able to process it?

Why do you think folinic acid blocks methylfolate? In 81% at least it appeared to not. If all goes well folinic acid is buffered and converted to methylfolate. Folinic acid is not only for nucletoides. It is storage form in the cell for folatea. Would expect much of it goes to methylfolate IF all is working well and no MTHFS defect. The really high dose are for cns penetration and saturation. Just like the r eally high doses if methylfolate used by some in these forums.